1-Hydroxybisphosphonates (BPs) are analogues of pyrophosphate where the P—O—P linkage is replaced by P—C—P. The carbon atom contains the 1-hydroxygroup and a variable side chain.1 The P—C—P bond is relatively stable towards chemicals and enzymatic hydrolysis. The powerful binding affinity towards bones is used in medicine for treatment in bone resorption and other bone disorders such as osteoporosis or tumor-induced osteolysis.2, 3 Bones are the most common sites for metastasis in patients with solid tumors arising from breast, prostate, lung, thyroid and kidney.4 The use of BPs has had a profound beneficial effect on the management of metastatic bone disease and the prevention of treatment-induced bone loss.5 BPs were also investigated for their potential use in parasital diseases.6, 7 The BPs bind strongly to hydroxylapatite and have been suggested as a bone-targeting vector in various tissue-specific contrast agents.8-12 Complexes of radioactive metal ions with BPs have been applied in bone cancer radiotherapy and in palliative settings for pain therapy associated with bone metastasis.13 Approaches for a chemotherapeutic bone targeting of cytostatics or protein proposed the conjugation of methotrexate14, 15, doxorubicine16 or albumin17 with BPs. Recent studies suggested that BPs have direct effects on tumor cells and may enhance the antitumor activities of cytostatics18-27. The potential usefulness of the BPs etidronate and zoledronate in decreasing or preventing inflammatory root resorption and replacement root resorption in replacement teeth was tested. Zoledronate was shown to prevent root resorption and to facilitate regeneration of periodontal tissues after replantation40.
Therapeutic nucleoside analogues like 2′-deoxy-5-fluorouridine (5-FdU), arabinofuranosyl cytidine (araC) and azidothymidine (AZT) are well-known compounds and their activity as antiviral and antitumor drugs is well-established since many years. Bone-targeting of those compounds has not been suggested so far.
There is a continuous need for further drugs allowing the targeted treatment of bone-related disorders like, for example, of bone tumors or metastatic bone tumors.